Choroidal neovascularization leads to hemorrhage and fibrosis, with resultant visual loss in a number of eye diseases, including age-related macular degeneration (AMD), ocular histoplasmosis syndrome, pathologic myopia and certain inflammatory diseases. Similarly, corneal and retinal neovascularization are involved in other eye diseases leading to vision loss.
AMD causes severe, irreversible vision loss and is the leading cause of blindness in individuals older than 50 years in the Western World. Most patients have the non-neovascular (“dry”) form, characterized by drusen and atrophic changes in the retinal pigment epithelium (RPE). Eighty to ninety percent of the severe vision loss due to AMD, however, is attributable to the form characterized by choroidal neovascularization (CNV), also called neovascular AMD. In the United States, between 70,000–200,000 individuals over the age of 65 develop the wet form of AMD every year. In CNV, the newly formed vessels have a tendency to leak blood and fluid, causing symptoms of scotoma and metamorphopsia. The new vessels are accompanied by proliferation of fibrous tissue. This complex of new vessels and fibrous tissue can destroy photoreceptors within 3 to 24 months. At the same time that existing CNV is destroying retinal tissue where it has formed, the lesion can continue to grow throughout the macula, resulting in progressive, severe and irreversible vision loss. Without treatment, most affected eyes will have poor central vision (≦20/200) within 2 years. In addition, when one eye of an individual develops CNV, the fellow eye has about a 50% chance of developing a similar CNV within 5 years.
Until recently, laser photocoagulation was the only treatment option available for CNV. Laser photocoagulation is limited to selected cases because the treatment destroys any viable photoreceptors overlying the area affected by CNV, often resulting in immediate visual acuity loss, especially when the lesion is subfoveal and the visual acuity is better than 20/200. For this reason, laser photocoagulation is only indicated for well-demarcated extrafoveal and juxtafoveal CNV as well as small, well-demarcated subfoveal lesions that have a pattern of classic CNV on fluorescein angiography. Recurrences following standard laser treatment of AMD cases occur in approximately 50% of cases. The recurrent CNV can lead to further vision loss, especially when the originally treated lesion was extrafoveal or juxtafoveal.
Photodynamic therapy (PDT) offers an alternative approach to selectively destroy CNV without significant destruction of overlying retina tissue, possibly by occluding the new vessels within the CNV. Photodynamic therapy is a two-step process consisting of an intravenous injection of a photosensitive compound (light-activated drug) followed by light application. The light sources used are non-thermal lasers or light emitting diodes (LEDs). The photosensitive compound preferentially accumulates in neovascular tissues, including the endothelial cells of choroidal neovascularization. In combination with localized light administration, this allows for selective treatment of the pathologic tissue. After exposure to light at a wavelength absorbed by the photosensitive compound, an energy transfer cascade is initiated, culminating in the formation of singlet oxygen which generates intracellular free radicals). These free radicals can disrupt cellular structures such as the cell membrane, mitochondria, and lysosomal membranes.
Occlusion of the neovasculature is presumed to be the major mechanism of PDT with verteporfin. Occlusion can occur through free radical damage to the endothelial cells, causing subsequent platelet adhesion and degranulation, and thrombus formation. A reduction in blood flow from the new vessels may lead to a confinement in the growth of the fibrovascular portion of the CNV with subsequent reduced risk of further vision loss.
Photodynamic therapy of neovascular conditions in the eye has been attempted over the past several years using various photosensitive compounds, e.g. porphyrin derivatives, such as hematoporphyrin derivative and porfimer sodium (PHOTOFRIN® Axcan Pharmaceuticals), phthalocyanines , green porphyrins (such as verteporfin, also known as BPD-MA), purpurins, such as tin ethyl etiopurpurin and texaphyrins, such as motexafin lutetium. The photosensitive compound verteporfin (Visudyne™, Novartis Ophthalmics) is the only photosensitive compound to have received regulatory approval for an ocular neovascular indication, and is now widely used for the treatment of AMD in patients with predominantly classic subfoveal CNV.
The approved protocol for treatment of CNV with verteporfin PDT (more fully described below) includes re-treatment of subjects as frequently as every three months if CNV leakage is detected upon fluorescein angiography. Although verteporfin PDT using this protocol closes neovasculature and prevents loss of visual acuity compared to placebo controls, in many subjects, there is still a decline in visual acuity from the baseline level following the initial treatment (Arch. Opthalmol. 117: 1329–1345). Although the dose ranges that are effective in humans were predicted using animal models (see for example, U.S. Pat. No. 5,798,349) it has been very difficult to optimize the treatment protocol in humans, so that the maximum benefit in the therapy can be achieved Consequently, there is a need for improving the PDT treatment of CNV and other neovascular conditions so that more visual acuity is preserved following the initial treatment.
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